Precocious puberty

- Dr. Raghavendra babu SII yr DNB (pead)

J.L.N hospital & research centre

Defination

• Precocious puberty is defined as onset of secondary sexual characteristics before age of 8 yrs in girls and 9 years in boys

• The variation in the age of the onset of puberty in normal children, particularly of different ethnicities, makes this definition somewhat arbitrary. It remains in use by most clinicians.

CONDITIONS CAUSING PRECOCIOUS PUBERTY CENTRAL (GONADOTROPIN DEPENDENT, TRUE PRECOCIOUS

PUBERTY)• Idiopathic• Organic brain lesions • Hypothalamic hamartoma• Brain tumors, hydrocephalus, severe head trauma, myelomeningocele• Hypothyroidism, prolonged and untreated

COMBINED PERIPHERAL AND CENTRAL• Treated congenital adrenal hyperplasia• McCune-Albright syndrome, late• Familial male precocious puberty, late

PERIPHERAL (GONADOTROPIN INDEPENDENT, PRECOCIOUS PSEUDOPUBERTY)

Girls

Isosexual (feminizing) conditions • McCune-Albright syndrome • Autonomous ovarian cysts• Ovarian tumors• Granulosa-theca cell tumor

associated with Ollier disease• Teratoma, chorionepithelioma• SCTAT associated with Peutz-

Jeghers syndrome• Feminizing adrenocortical

tumor • Exogenous estrogens

BoysIsosexual (masculinizing) conditions • Congenital adrenal hyperplasia• Adrenocortical tumor• Leydig cell tumor• Familial male precocious puberty

IsolatedAss.with pseudohypoparathyroidism

• hCG-secreting tumors Central nervous systemHepatoblastomaMediastinal tumor associated with

Klinefelter syndrome

• Teratoma• Glucocorticoid receptor defect • Exogenous androgen

Heterosexual (masculinizing)

conditions • Congenital adrenal hyperplasia • Adrenal tumors• Ovarian tumors• Glucocorticoid receptor defect• Exogenous androgens

Heterosexual (feminizing) conditions

• Feminizing adrenocortical tumor• SCTAT associated with Peutz-

Jeghers syndrome• Exogenous estrogens

INCOMPLETE (PARTIAL) PRECOCIOUS PUBERTY•Premature thelarche•Premature adrenarche

Approach to precocious puberty

Pointers in History:o Age of onset earlier the age of onset greater the like hood of

underlying organic disease

Idiopathic GDPP onset after age of 6 yrs slow progression lack of neurological features

• hypothalamic hamartoma, a neuronal migration defect is the commonest cause of organic central precocious puberty Early age of onset

rapid progression of puberty Seizures and uncontrolled laughter

(gelastic epilepsy)o SEX: GDDP is 5 times more common in girls, most

often Idiopathic. in boys, less common, usually ass. With

underlying pathology in 2/3rd

oPubertal progression: in GIPP , there is deviation from the normal pubertal progression Normal pubertal progression:In girls: Thelarche pubarche menacheIn boys: testicular enlargement (>4ml) pubarche development of ext. genitalia.

o Evidence of Linear growth accelaration:precocity is ass. with growth spurt, except in

hypothyroidism and sellar mass with G.H deficiency.

o H/O past CNS infections, headaches, visual disturbances, personality changes, developmental delay and seizures points underlying neurological disorder.

o H/o of Drug exposure

o Symptoms suggestive of Hypothyroidism

o H/o of precocious puberty in boys and genital ambiguity in girls in same family suggests Congenital adrenal hyperplasia

o family H/O of precocious puberty limited to males would suggest familial testotoxicosis.

Physical examination

• Height, weight, Height velocity (cm/yr)

• SMR staging (tanner’s staging )

testicular volume estimationPre-Pubertal testicular volume(<4ml) is characteristic of

C.A.H and adrenal tumours.Unilateral testicular enlargement is seen in testicular

tumours.Pubertal testicular volume Central precocious puberty

• Evaluate Androgen effects

AcneHirutismIncrease muscle massclitoromegaly

Estrogen effectsBreast developmentChanges in vaginal mucosa

• Inspection of skin café au lait macules characteristic of McCune-Albright syndrome and neurofibromatosis.Hyper pigmentation + Hypertension C.A.H

• Neurological examination including fundus and perimetry

• Examination for signs of Hypothyroidism.

•Abdominal examination for adrenal and ovarian masses.

Investigations

Basic radiology : Bone age for skeletal maturation

Advanced in all cases of precocious puberty

Delayed HypothyroidismNormal incomplete precocious puberty

Pelvic and Abdominal Usg : to evaluate the size and morphology of uterus, ovaries and adrenals.

Hormonal evaluation:random S. Luteinizing hormone (LH) is good

screening test for central precocious puberty

levels of 0.3 IU/L or more are pubertal

If random s.LH levels < 0.3 IU/L

Stimulation test with Aqueous Leoprolide acetate (GNRH) (20 mg/kg ) S.C/I.M

60 min s.LH value > 3.3 – 5.0 IU/L suggest GDPP (CPP)

CT or MRI Brain

Thyroid Function Tests – to R/O Hypothyroidism

Further tests for Gonadotropic independent precocious puberty :

s.DHES (dehydroepiandrosterone sulfate)Elevated in premature adrenarche.Very high in virilizing adrenal tumours.

Basal serum 17-OH Progesterone (and/or) to R/O C.A.H

ACTH stimulated 17-OH Progesterone

Serum/C.S.F hCG levels – if hCG secreating tumour is suspected in boys with precocious puberty.

Testicular sonography – if tumours suspected

TFT

Skeletal survey : in suspected cases of Mc Cune – Albright syndrome to look for fibrous dysplasia.

Management

Surgical :tumours of ovaries, testes, adrenals – remove

surgically.ovarian cysts > 3cm in size – Explore surgically.

surgery for Hypothalamic hamartomas is hazardous & not recommended as they do not grow and become malignant

germ cell tumours, pineal tumours , hCG producing suprasellar tumours are treated with radiotherapy

Medical:Progressive central precocious puberty

Indication of treatment : predicted adult height is less psychologically distressing to the child rapid progression GnRH Agonists

Inj.Leuprolide (0.5 – 0.3 mg/kg/dose) either monthly or 3 monthly depot

Acts by continuous stimulation of pituitary gonadotropes thereby desensitization and decrease in release of L.H

Inj. Medroxy-progesterone at dose of 150/m2 I.M is added every 15days for first 6 weeks , to counter the possible stimulatory effect of GnRH agonist initiation.

the Rx is discontinued at chronological age of 11 yrs (12yrs in boys) and Bone age of 12.5 yrs (17.5 yrs in boys).

Rx of gonadotropin independent precocious puberty : Hypothyroidism – thyroxine replacement Mc Cune Albright syndrome :

inhibiting estrogen productionAromatase inhibitor- Anastrazole, LetrozoleBlock estrogen action – Tamoxifen

Testotoxicosis - Antiandrogens

psychological support :

Hypothyroidism & precocious puberty• Precocious puberty in a child with untreated hypothyroidism

and a prepubertal bone age presents a strikingly unphysiologic association, yet it is common and occurs in as many as 50% of children with severe hypothyroidism of long duration.

• The cause of the hypothyroidism is usually Hashimoto thyroiditis, which often goes undiagnosed, especially in children with special needs such as those with trisomy 21.

• Plasma levels of thyroid-stimulating hormone (TSH) are markedly elevated, often >500 ?U/mL

Plasma levels of thyroid-stimulating hormone (TSH) are markedly elevated, often >500 ?U/mL. and plasma levels of prolactin are

mildly elevated.

the massively elevated concentrations of TSH appear to interact with the FSH receptor (specificity spillover), thus inducing FSH-like effects in the absence of LH effects on the gonads

unlike in central precocious puberty, testicular enlargement occurs without substantial testosterone secretion in boys. Thus, the precocious puberty associated with hypothyroidism behaves as an incomplete form of gonadotropin-dependent puberty. Prolactin raise stimulate thelarche.Treatment of the hypothyroidism results in rapid return to normal of the biochemical and clinical manifestations. Macroorchidism (testicular volume >30 mL) can persist in men despite adequate thyroxine therapy.